System and method for biphasic transdermal iontophoretic delivery of therapeutic agents for the control of addictive cravings

ABSTRACT

Embodiments of the invention provide methods for the transdermal delivery of therapeutic agents for the treatment of addictive cravings e.g., nicotine compounds for the treatment of nicotine cravings from tobacco use. An embodiment of a method for such delivery comprises positioning at least one electrode assembly in electrical communication with a patient&#39;s skin. The assembly includes a solution comprising a therapeutic agent which passively diffuses into the skin. A dose of agent is delivered from the assembly into the skin during a first period using a first current having a characteristic e.g., polarity and magnitude, to repel the agent out of the assembly. During a second period, a second current having a characteristic to attract the agent is used to retain the agent in the assembly such that delivery of agent into skin is minimized. A dose of agent may be delivered on demand by an input from the patient.

RELATED APPLICATIONS

This application claims the benefit of priority of Provisional U.S.Patent Application Ser. No. 61/518,486, entitled “BIPHASIC TRANSDERMALIONTOPHORETIC SYSTEM FOR THE TRANSDERMAL DELIVERY OF THERAPEUTIC AGENTSFOR THE CONTROL OF ADDITIVE CRAVINGS” filed May 6, 2011; which is fullyincorporated by reference herein for all purposes.

This application is also a continuation-in-part of U.S. patentapplication Ser. No. 12/537,243, entitled “Iontophoretic System ForTransdermal Delivery Of Active Agents For Therapeutic And MedicinalPurposes”, filed Aug. 6, 2009, which claims the benefit of priority toProvisional U.S. Patent Application No. 61/152,251, entitled “Kit,System and Method for Transdermal Iontophoretic Delivery of TherapeuticAgents”, filed Feb. 12, 2009; both of which are fully incorporated byreference herein for all purposes.

This application is also a continuation-in-part of U.S. patentapplication Ser. No. 13/430,662, entitled “System And Method ForBiphasic Transdermal Iontophoretic Delivery Of Therapeutic Agents”,filed Mar. 26, 2012, which claims the benefit of priority of ProvisionalU.S. Patent Application Ser. No. 61/465,896, entitled “BiphasicTransdermal Iontophoretic System For The Transdermal Delivery OfTherapeutic Agents” filed Mar. 24, 2011; both of which are fullyincorporated by reference herein for all purposes.

This application is related to U.S. patent application Ser. No.12/898,671, entitled “Patch and Patch Assembly For IontophoreticTransdermal Delivery Of Active Agents For Therapeutic And MedicinalPurposes” filed Oct. 5, 2010, which claims the benefit of priority ofU.S. Provisional Patent Application Ser. No. 61/249,247 filed Oct. 6,2009 both of which are fully incorporated by reference herein for allpurposes.

FIELD OF THE INVENTION

Embodiments described herein relate to assemblies and methods fortransdermal drug delivery. More specifically, embodiments describedherein relate to assemblies and methods for iontophoretic transdermaldelivery of drugs and other therapeutic agents. Still more specifically,embodiments described herein relate to assemblies and methods for usingiontophoretic transdermal delivery of therapeutic agents to treataddictive cravings.

BACKGROUND

Cigarette and other forms of tobacco addiction affect millions ofAmericans. It destroys quality of life, causes many mortal diseasesincluding heart and lung diseases and multiple forms of cancer.According to the CDC, smoking causes nearly 500,000 deaths each year inthe U.S. alone due to heart and lung disease and numerous forms ofcancer. Other forms of tobacco use such as cigar and pipe smoking aswell as chewing tobacco are also responsible for countless deaths eachyear due to mouth and throat and other forms of cancer. Cigarettesmoking and other forms of tobacco addiction are all due to the presenceof nicotine which is a highly addictive alkaloid substance found in thetobacco plant. The addiction is due to number of psychoactive effectsthat nicotine has on the brain including feeling of satisfaction, calm,relaxation, etc. In case of cigarettes, matters are made worse by thefact that tobacco companies actually adjust the dose of nicotine incigarettes to maximize addictive behavior. They do this in part bydesigning cigarettes to give the smoker an immediate spike of nicotineupon the first several puffs.

Many smoking cessation program involve stopping smoking altogether(i.e., going cold turkey). However, one of the most difficult aspects ofthis or other forms of tobacco cessation is the craving for nicotine andthus a cigarette created when the user suddenly stops smoking. There areseveral nicotine delivery products to address this pro problem which donot involve smoking. Two of the more popular forms used in smokingcessation programs include nicotine containing transdermal drug deliverypatches nicotine containing gum. However both have a number oflimitations. First, neither is able to mimic the rapid or spike dosedelivery of nicotine achieved from smoking a cigarette. Consequently,the smoker doesn't get the same psychoactive effect and as a result theuser can still develop cravings even when they are receiving nicotinefrom one or both products. Further, for these same reasons, neither maybe effective for the treatment of breakthrough cravings. Breakthroughcraving is a craving that comes on suddenly for short periods of timeand is not easily controlled. For cigarette smokers, the characteristicsof breakthrough cravings may vary from person to person depending upontheir smoking habits including the number of cigarettes they weresmoking each day, years of smoking and overall brain chemistry. Netherapproach can treat such cravings since they deliver fixed amounts ofnicotine over an extended period of time and cannot be adjusted for agiven user. Both methods are susceptible to excessiveself-administration from the user applying multiple patches and/orchewing multiple lozenges. The user is also susceptible to varyingdelivery in the case of transdermal patches since manufactures make onesize fits all transdermal fixed dose nicotine patches which don'taccount for differences between users. Further, transdermal patches alsosuffer from the limitation of over-delivery since the user continues toreceive nicotine via passive diffusion from the patch even after theircraving has been satisfied. This can result in the user habituating toeven higher doses of nicotine. Thus, there is a need for improvedmethods of nicotine delivery for the treatment of cigarette/nicotinecravings occurring smoking cessation plans. The same need also appliesto other forms of tobacco use including cigar, pipe and chewing tobaccowhich result in nicotine addiction,

Transdermal iontophoresis is a non-invasive method of propelling highconcentrations of a drug or other therapeutic agent through the skin ofa human or other animal by repulsive electromotive force using a smallelectrical charge. The electrical charge repels ionized (i.e., charged)forms of the drug or other therapeutic agent. Using such an approach,doses of pain medication can be delivered to the patient using a skincontacting patch containing pain medication that has been dissolved in asolution disposed within the patch. The application of a current causesthe dissolved medication to be propelled from the solution through acontacting layer of the patient and into the skin. However,over-administration/overdose remains a problem for such devices due tothe fact that the pain medication continues to passively diffuse fromthe patch reservoir into the patient even when the iontophoretic currentis off due to concentration gradients between the patch and the skin(under the principles of Fickian diffusion). Also, there is nothing tostop the patient from overdosing themselves by reactivating the deviceor even leaving the current on continuously to give themselvesrepetitive or even continuous doses. Improved systems and methods areneeded for preventing over-administration of drugs due to passivediffusion as well as excessive administration by the patient.

BRIEF SUMMARY

Embodiments of the invention provide methods and assemblies for thetransdermal delivery of drugs and other therapeutic agents to humans,mammals and other animals. Many embodiments provide a biphasictransdermal iontophoretic system having a delivery current to deliverdoses of a therapeutic agent over a delivery period and a holdingcurrent to substantially halt or reduce the delivery of agent during anon-delivery period. Such embodiments can be configured to allow forrepetitive cycles of delivery and non-delivery of drugs and othertherapeutic agents to treat various conditions including for example,addictive cravings. Further, various embodiments provide systems andmethods allowing for on-demand initiation of a delivery period (e.g., bythe patient, caregiver or other person) to allow for treatment ofvarious acute conditions such as craving control, pain, nausea (e.g.,chemotherapy induced), migraine headache and other conditions. Inparticular embodiments such systems and methods can be configured foruse in the delivery of various nicotine compounds (e.g., nicotine salts)for treatment of a patient's cigarette/nicotine cravings occurringsmoking cessation or reduction. Cigarette/nicotine craving refers to thepatient's craving for a cigarette and/or nicotine from a cigarette whichmay occur as a result of the patient ceasing or reducing his or her useof cigarettes. Such embodiments can also be adapted for treatment ofcravings resulting from other forms of tobacco addictions such as thosecravings occurring from other forms of inhaled tobacco use such as pipe,cigar or electronic cigarette use as well as use of chewing tobacco. Inother particular embodiments, such systems and methods can be adaptedfor delivery of other compounds used for the treatment of other chemicalbased addictions such as methadone (including its analogues andderivatives) or other synthetic opiode for the treatment of heroin orother opiode-based addiction as well as various compounds for thetreatment of cocaine addiction.

Still other embodiments of systems and methods of the invention providefor controlled initiation of a delivery period and/or cycles of deliveryand non-delivery by a controller such as a microprocessor or othercontroller known in the art (e.g., an analogue controller). Suchembodiments can be configured for the cyclical delivery of a variety oftherapeutic agents including, for example, various nicotine compounds(e.g., nicotine analogues and their salts) for the treatment of nicotinecravings resulting from cessation/reduction of various forms of tobbacouse, e.g., cigarette smoking. Further, such embodiments are particularlyuseful for the delivery of therapeutic agents where the time course ofdelivery of the agent needs to be controlled to produce a desiredtherapeutic effect, and/or to minimize adverse effects to the patient(e.g., re-habituation to higher levels of nicotine due to over delivery)Such controlled initiation (either of a delivery period or cycle ofdelivery and non-delivery periods) can be incorporated into a deliveryregimen which can be programmed into the controller either directly,wirelessly or by means of a memory device operably coupled to thecontroller. The system can be configured to allow the program to beselected by a doctor, pharmacist, or other medical care provider. Theselection can be done directly by the medical care provider via an inputdevice (e.g., a touch screen) coupled to the controller or wirelesslyusing a wireless device such as a cell phone, tablet device or likedevice. In either case, lockout codes can be employed to prevent anyonebut the medical care provider from entering or changing a particulardelivery regimen.

One embodiment provides a method for the transdermal iontophoreticdelivery of a therapeutic agent for treatment of addictive cravings,such as a nicotine compound for the treatment of addictive cravings forcigarettes, cigars or other tobacco product occurring during cessationor reduction in the use of the tobacco product. The method comprisespositioning at least one electrode assembly in electrical communicationwith a patient. The electrode assembly includes a skin contacting layerand a solution having a dissolved therapeutic agent (e.g., a salt ofnicotine or a nicotine analogue) having an electrical charge, whereinthe dissolved agent passively diffuses into the skin without theapplication of an external force. A first dose of agent (such asnicotine or a nicotine analogue) is delivered from the electrodeassembly into the skin during a first period using a first currenthaving a polarity and voltage to repel the agent out of the assembly.The dose may be delivered continuously or in a series of bursts, forexample, to mimic or simulate the nicotine delivery profile frompatient's taking puffs on cigarettes. Such bursts may have a squarewave, half sign wave, trapezoid other shape. Other delivery patterns forsimulation of delivery profiles from other forms of tobacco use (e.g.,cigar, electronic cigarette, chewing tobacco) or other addictivesubstances are also contemplated. Also, the dose can be titrated to thecharacteristics of a particular patient, such as their weight andsmoking habits (e.g., number of cigarettes smoked per day and how muchthey have de-habituated). During a second period, a second currenthaving a polarity and voltage to attract the agent is used to retain theagent in the assembly such that delivery of the agent into the skinduring the second period is minimized so as to reduce the likelihood ofunwanted and/or over delivery of the agent. For embodiments deliveringnicotine compounds to treat smoking addiction, this minimized deliveryprevents the patient from experiencing the psychoactive effectsassociated with nicotine during this second period which can cause themhabituate to higher levels of nicotine and/or slow their progress inde-habituating. The first period comprises a delivery period and thesecond period comprises a non-delivery period, which together, comprisea delivery cycle period. The delivery cycle period can then be repeatedas needed to reduce the addictive cravings in the patient. In particularembodiments, one or more delivery parameters such as the dose deliveredduring a delivery period and the length of the delivery and non-deliveryperiods can be determined or titrated based upon one or more parametersof the patient's smoking pattern. Such parameters can include, forexample, the duration of each puff, puff volume, the interval betweenpuffs and total number of puffs. In this way, the delivery profile ofnicotine compound delivered by embodiments of the invention can moreclosely approximate or mimic the nicotine delivery profile from thepatient's actual use of cigarettes (or other form of inhaled tobacco).In use, this approach can reduce nicotine cravings since the nicotinedelivered during a delivery period/cycle more closely approximates thatwhich the patient gets from the smoking of a cigarette or other form oftobacco.

In related embodiments, the dose of the therapeutic agent duringdelivered during a delivery period and/or during a delivery cycle can bedecreased over time to de-habituate the patient from their addiction. Inspecific embodiments, the dose of therapeutic agent can be re-titrated(after a first initial titration) to reflect the patient's progress intheir addictive behavior cessation plan. For example, in the case of acigarette smoking cessation plan, a delivered dose of nicotine can bere-titrated based on one or more of the number of days since the patientstarted the plan, the number of cigarettes they are currently smoking,the change versus when they started the smoking cessation/reductionprogram and the number and of severity of cravings the patient iscurrently experiencing and the change versus when they started thesmoking cessation/reduction program.

In use, these and related embodiments provide an approach for thecontrolled transdermal delivery of a therapeutic agent for the treatmentof addictive cravings (e.g., nicotine and opiode cravings) whichprovides several benefits. First, through the use of a titrated and/orburst dosing it more closely approximates the dose delivered during theaddictive behavior (e.g., smoking a cigarette) producing a similarpsycho-active response as the behavior thus, reducing cravings. Second,the likelihood of over delivery and/or the patient habituating tounwanted delivered doses is reduced since passive diffusion duringnon-delivery periods is minimized. One or both of these factors can helpa patient quit an addictive behavior such as cigarette smoking fasterand with greater success (e.g., reduced likelihood of relapse) overconventional approaches.

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross sectional view showing the three main layers of theskin, the epidermis, the dermis and subcutaneous tissue as well as thepassageways into the skin.

FIG. 2 is a lateral view of an embodiment of a system for thetransdermal iontophoretic delivery of various therapeutic agents usingdelivery and lateral electrodes.

FIG. 3 a is a schematic side view showing placement of an embodiment ofa transdermal iontophoretic patch device on the surface of the skin,wherein the device comprises an active electrode assembly and a returnelectrode assembly.

FIG. 3 b is a schematic side view showing placement of an embodiment oftransdermal iontophoretic patch device on the surface of the skin,wherein the device comprises two active electrode assemblies.

FIGS. 4 a and 4 b are side and top views showing an embodiment of a skinpatch including an active electrode and lateral electrodes.

FIG. 5 a is a top down view showing an embodiment of an on demanduser-activated transdermal delivery system including a patch assembly.

FIGS. 5 b, 5 c and 5 d are time sequence graphs illustrating anembodiment of a patient controlled or other “on-demand” biphasictransdermal iontophoretic delivery system having a delivery current anda holding current so as to cycle between delivery periods andnon-delivery periods of a therapeutic agent such as nicotine for thetreatment of nicotine cravings from tobacco use. FIG. 5 b shows anactivation signal for initiating a drug delivery cycle, the signalgenerated by a patient activated device or other signal generationmeans; FIG. 5 c shows an embodiment of a current waveform initiated bythe activation signal the waveform having a delivery current and holdingcurrent; FIG. 5 d shows an embodiment of a drug delivery profilecorresponding to the periods of delivery current and holding current.

FIGS. 6 a and 6 b are perspective views showing an embodiment of asystem/patch assembly for iontophoretic transdermal delivery of atherapeutic agent (such as a nicotine compound for the treatment ofnicotine cravings from tobacco use) including a patch and an electronicsassembly, FIG. 6 a shows a top view, FIG. 6 b shows a bottom view. FIG.6 c is a block diagram of an embodiment of the electronics assemblyincluding a controller, current source and current switching device.

FIG. 7 a is a perspective view showing placement of the embodiment ofFIGS. 6 a and 6 b on an example site on the skin of a user.

FIG. 7 b is a lateral view showing an embodiment of a patch assemblyhaving a curved contour positioned at a tissue site having a curvedcontour.

FIGS. 8 a through 8 f illustrate various waveforms or current outputvariations that can be used to promote various characteristics ofembodiments of the transdermal iontophoretic delivery system.

FIG. 8 g illustrates an embodiment of a burst mode deliveryprofile/curve for burst mode delivery of a nicotine compound. FIG. 8 hillustrates the resulting nicotine delivery curve and comparison to thedelivery curve for smoking a cigarette or other inhaled form of tobacco.

FIG. 8 i illustrates different embodiments of burst mode deliverycurves.

FIG. 9 is a block diagram of a transfer function used to model anembodiment of the transdermal iontophoretic delivery system used in theexample.

FIGS. 10 a and 10 b are plots of delivered therapeutic agent versustime. FIG. 10 a shows the cumulative input vs. the estimated systemresponse based on an optimum cross-correlation FIR filter response ofthe measured system response; FIG. 10 b plot shows the density input vs.the estimated system response based on an optimum cross-correlation FIRfilter response of the measured system response.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments described herein provide a device, system and methodfor the transdermal iontophoretic delivery of various therapeutic agentsincluding therapeutic agents for the treatment of various addictions.Such addictions can include addictions to various chemical compounds,e.g., nicotine and the addictive delivery modes for that compound, e.g.,cigarette smoking. Many embodiments provide devices, systems and methodsfor the biphasic transdermal delivery of various therapeutic agentsincluding therapeutic agents for the treatment of various addictions andaddiction related cravings. Such therapeutic agent for the treatment ofaddiction related cravings can include without limitation, nicotinecompounds for the treatment of nicotine cravings resulting fromcigarette or other tobacco addiction (e.g., cigar, pipe, chewingtobacco, etc.); methadone and other synthetic opioid for the treatmentof cravings resulting from heroin addiction to heroin or other opioid;and one or more of Acetylcysteine, Baclofen, Bupropion, Vanoxerine, andVigabatrin or other related compound for the treatment of cravingsresulting from cocaine addiction.

As used herein, the term transdermal delivery refers to the delivery ofa compound, such as a drug or other therapeutic agent, through one ormore layers of the skin (e.g., epidermis, dermis, etc.). Referring nowto FIG. 1, the layers of the skin include the epidermis EP, dermis D andsubdermis SD. The upper most layer of the epidermis includes the stratumcorneum SC, a dead layer of skin (having a thickness of about 10 to 40μm) and the viable epidermis EP. Transdermal delivery can proceed by oneof the three passage ways into the skin, via 1, the sweat pores SP, 2,the hair follicles HF or via permeation 3 through the epidermis EP(starting at the stratum corneum) and the dermis.

Iontophoresis is a non-invasive method of propelling high concentrationsof a charged substance, known as the active agent, transdermally byrepulsive electromotive force using a small electrical charge. Theactive agent can include a drug or other therapeutic agent. The chargeis applied by an electrical power source to an active electrode assemblyplaced on the skin which contains a similarly charged active agent and asolvent in which it is dissolved. Current flows from the electrodeassembly through the skin and then returns by means of a return orcounter electrode assembly also placed on the skin. A positively chargedelectrode assembly, termed the anode will repel a positively chargedactive agent, or anion, into the skin, while a negatively chargedelectrode assembly, termed the cathode, will repel a negatively chargedactive agent, known as a cation, into the skin.

Referring now to FIGS. 2-4 b, an embodiment of a system 5 for thetransdermal iontophoretic delivery of a therapeutic agent 51 to a tissuesite TS (such as the arm A) also referred to as a delivery site TS, onthe skin S of patient may comprise at least two electrode assemblies 14including an active electrode assembly 20 and a return electrodeassembly 30 and a power supply 100. Active electrode assembly 20 is usedto deliver the therapeutic agent through skin S via current delivered tothe skin from power supply 100. Return electrode assembly 30 provides areturn path for current (e.g., current 60) to power supply 100.Collectively, the active and return electrode assemblies 20 and 30comprise a transdermal iontophoretic delivery device 10 also describedherein as patch device 10. In embodiments using an alternating current,both electrode assemblies 14 can be configured as active and returnelectrode assemblies 20 and 30 depending on the direction of currentflow. In some cases for sake of brevity, electrode assembly 14, activeelectrode assembly 20 and/or return electrode assembly 30 will sometimesbe referred to as electrode 14, active electrode 20 and return electrode30 respectively.

In many embodiments, the electrode assemblies 14 (e.g., active andreturn assemblies 20 and 30) comprise or are otherwise disposed on oneor more patches 15 configured to be applied to the skin surface. Patches15 are conformable to a contour CR of a skin surface S and can befabricated from layers of elastomeric or other flexible polymermaterial. In some embodiments, two or more electrode assemblies 14including active and return electrode assemblies 20 and 30 can be placedon a single patch 15. In other embodiments, system 5 can includeseparate patches 15 for electrode assemblies 14, for example, a firstpatch 15′ for the active electrode assembly 20 and a second patch 15″for the return electrode assembly 30. In other embodiments, three ormore patches 15 can be used so as to have either multiple activeelectrode assemblies 20 or return electrode assemblies 30 or both. Forexample, in one embodiment, system 5 can comprise three patches 15;including two patches containing active electrode assemblies 20 and athird patch 15 containing a return electrode assembly 30. Othercombinations of multiple patches and electrode assemblies are alsocontemplated, e.g., four patches, two for active electrode assemblies 20and two for return electrode assemblies 30.

In many embodiments, active electrode assembly 20 can comprise areservoir 21 for the therapeutic agent, a tissue contacting porousportion 24 in fluidic communication with the reservoir, an adhesiveportion 25 for adhering the assembly to the skin, and an electricalconnector 26 for coupling the electrode assembly 20 to an electricalpower supply 100 as is shown in the embodiment of FIG. 2. Reservoir 21can be sized for the particular dose of therapeutic agent to bedelivered. In various embodiments, the power supply 100 can includevarious features to facilitate use by medical personnel both in ahospital setting and in the field. For example, the power supply caninclude or be configured to be coupled to a bar code reader (not shown)for reading bar codes positioned on one or more of electrode assemblies14, patches 15 or power supply 100.

Tissue contacting portion 24 is also electrically conductive (hereinconductive) so as to function as an active electrode 20 and/or returnelectrode 30. This can be achieved by fabricating tissue contactingportion 24 from conductive porous materials (e.g., conductive carbon orother conductive fibers) and/or by having it become wetted with aconductive embodiment of solution 54 (the conductivity being due totherapeutic agent 51 or various electrolytes added to the solution 54).Connector 26 can extend into or otherwise make electrical contact withtissue contacting portion 24 so to be electrically coupled to portion24. In some embodiments, connector 26 can be coupled to a conductiveelement 28 positioned within the electrode assembly 14 and coupled toconductive porous portion 24. One or more of conductive element 28,conductive layer 34 (described below) as well as lateral electrodes 40(also described below) can comprise various conductive materialsincluding stainless steel, carbon, silver chloride (AgCl) or otherconductive materials known in the art.

Typically, adhesive portion 25 will surround the perimeter 24 p ofporous portion 24 as is shown in the embodiment of FIGS. 4 a and 4 b,though other arrangements are also contemplated. In various embodiments,porous portion 24 can comprise a porous layer 24 that in turn comprisesvarious porous materials including polymers foams, membranes or weavesof polymer fibers known in the art including polyesters, PETs and likematerials. Adhesive portion 25 may be attached to porous layer 24 andinclude various releasable adhesives known in the art. The adhesiveportion 25 can comprise an adhesive layer 25 a, such as one or morereleasable adhesives attached to a substrate layer 25 s, which cancomprise various hydrogels, polyurethanes, silicones or like polymericmaterials. The size and configuration of adhesive portion 25 can beadapted for the particular skin location (e.g., arm vs. leg, amount ofhair, etc.) and type of skin (e.g., pediatric vs. geriatric etc., amountof hair, etc.).

Typically, the therapeutic agent 51 will be dissolved in a therapeuticagent solution 54, also described as therapeutic agent composition 54which is used to fill reservoir 21. In various embodiments solution 54comprises an aqueous solution and will sometime be referred to herein asaqueous solution 54. In addition to therapeutic agent 51, solution 54can include one or more pharmaceutical excipients 52 such aspreservatives (e.g., citric acid) as is discussed in more detail below.The viscosity of solution 54 can be adjusted to have the solutionreadily wick from reservoir 21 into porous layer 24. Solution 54 can bepreloaded into the reservoir 21 at the factory or can be added bymedical personnel prior to use through means of a port 22, such as aself-sealing port (allowing injection of liquid through the port) whichis coupled to reservoir 21 via means of a channel 27 as is shown in theembodiment of FIG. 3 b. Suitable therapeutic agents 51 can include,without limitation, nicotine compounds for the treatment of nicotinecravings from smoking or other tobacco addition; methadone compounds forthe treatment of heroin (or other opioid) cravings and withdrawalsymptoms from heroin addiction and one or more of Acetylcysteine,Baclofen, Bupropion, Vanoxerine, and Vigabatrin for the treatment ofcocaine cravings and withdrawal resulting from cocaine addiction. Othertherapeutic agents 51 for the treatment of craving and withdrawal fromother chemical dependent addictions are also contemplated. Still othertherapeutic agents 51 can include ferric pyrophosphate or other ironcontaining compound for the treatment of iron deficient anemia, insulinor various glucagon like peptides for treatment of diabetes or otherblood sugar regulation disorder, fentanyl or other opioid compound forpain management and various chemotherapeutic agents for the treatment ofcancer.

The return electrode assembly 30 comprises a tissue contactingconductive layer 34, an adhesive layer 35 and a connector 26 forcoupling the electrode assembly to the electrical power source. In manyembodiments, the return electrode assembly 30 can have substantially thesame elemental configuration as active electrode assembly 20 (e.g., areservoir 21, conductive tissue contacting layer 24) so as to functionas an active electrode assembly as is shown in the embodiment of FIG. 3b.

In many embodiments, patch 15 also includes one or more pair ofelectrodes known as lateral electrodes 40. Lateral electrodes 40 areplaced on either side of porous portion 24 at a selectable distance fromthe perimeter 24 p of porous portion 24 as is shown in the embodimentsof FIGS. 3 a-3 b and 4 a-4 b. Lateral electrodes 40 can comprise variousconductive materials including metals, graphite, silver chloride andother like materials. In various embodiments, all or a portion oflateral electrode 40 can include an insulative coating so as to be acapacitively coupled electrode that delivers current to the skin viacapacitive coupling. Lateral electrodes 40 are also electricallyisolated from electrodes 20 and 30 and will typically include their ownwave form generator circuits.

The lateral electrodes 40 are arranged with respect to porous portion 24such that they result in a conductive pathway 104 which goes through theskin S underlying portion 24 and is substantially parallel to the skin.Embodiments of patch 15 that employ lateral electrodes 40 with deliveryelectrodes 20, allow for the flow of two currents, a first current 60and a second current 70. First current, 60 flows between electrodes 20and 30 and serves to provide an electromotive force which acts to drivethe therapeutic agent 51 into and across the layers of the skin S. Thesecond current 70, known as sieving current 70, provides anelectromotive force that acts on the therapeutic agent 51 in a directionparallel to the skin S so as to cause oscillation of therapeutic agent51 in a direction parallel to skin S. This oscillation acts to sieve thetherapeutic agent through pathways of lesser or least diffusionalresistance in the skin. For embodiments where second patch 15″ containslateral electrodes 40 and is used to deliver therapeutic agent, a thirdcurrent 70′ can be delivered from lateral electrodes on the second patch15″ to also create an electromotive driving force to oscillate thetherapeutic agent substantially parallel to the skin surface underneaththe second patch 15″. Further description of the arrangement and use oflateral electrodes 40, including their use in generating a sievingcurrent, is found in U.S. patent application Ser. No. 12/658,637, filedFeb. 10, 2010 which is incorporated by reference herein in its entirety.

Referring now to FIGS. 5 a-5 d, various embodiments of the invention foruse in on demand transdermal delivery of a therapeutic agent will now bedescribed. Such embodiments include systems 5′ and methods for on demanddelivery of therapeutic agents 51. As used herein, the term “on demand”;refers to the ability of the patient or other person (e.g., a medicalcare provider) to initiate the delivery of therapeutic agent. Thisincludes the initiation of a therapeutic agent delivery period and/orcycle of therapeutic agent delivery periods described below. Theinitiation of any of these can be a signal/input from a patientactivation device such as a push button device and/or a signal receivedfrom a wireless device such as cell phone or other RF-enabled device.Such “on demand” embodiments provide for one or more of the following:i) the ability for the patient, other user or a controller/machine toinitiate the delivery of therapeutic agent 51 to the patient; and ii)the ability to stop or otherwise limit the passive diffusion oftherapeutic agent 51 during periods of time when an iontophoreticcurrent is not supplied to patch assembly 15 cp. In many embodiments, ondemand transdermal delivery can be implemented by use of a biphasictransdermal iontophoretic delivery system 5″ (biphasic transdermaliontophoretic delivery is defined and further described below). Suchembodiments are particularly useful for the delivery of therapeuticagents 51 p (herein after medication 51 p) for the treatment ofaddictive cravings, such as nicotine or other nicotine compound for thetreatment of cravings (e.g., for cigarettes) from tobacco addiction.However, it should be appreciated that embodiments of such a system 5″can be used for the delivery of any therapeutic agent 51 describedherein or known in the art for the treatment of any number ofconditions.

Referring now to FIG. 5 a an embodiment of an “on demand” transdermaldelivery system 5′ will now be described. The system may be configuredfor on demand delivery of therapeutic agent 51 by the patient and/or amedical care provider. System 5′ may also be configured as a biphasictransdermal iontophoretic delivery system 5″ described herein, forexample, through the use of a control program 93 p described below. Thesystem 5′ includes a patch assembly 15 cp including a patch 15,electrodes 14, therapeutic agent reservoir 21 and electronic module orsection 90 including a user activated device 91 (also referred to asactivation device 91) for allowing the patient or other user to initiatedelivery of therapeutic agent 51. Electrodes 14 will typically include adelivery or active electrode 20 and a return electrode 30 as describedherein. Active electrode 20 is configured to be in fluidic communicationwith a therapeutic agent reservoir 21 for storing a supply oftherapeutic agent 51. As described herein, in many embodiments,therapeutic agent 51 will be dissolved in a solution 54 (contained inreservoir 21) so as to be in ionic form. According to one or moreembodiments, solution 54 containing therapeutic agent 51 can be loadedinto reservoir 21 at the factory and/or at the pharmacy by a pharmacistbefore pickup by the patient. According to other embodiments,therapeutic agent 51 is stored in reservoir 21 in solid form and liquidcomprising solution 54 is added to the reservoir by the user or medicalcare provider immediately prior to use.

In various embodiments, patch 15 can have a substantial oval shape 15 oincluding, for example, peanut or cassini-shaped ovals 15 oc having sideportions 15 s and a tapered center portion 15 c as is shown in theembodiment of FIG. 5 a. Electrodes 14 including active electrode 20 andreturn electrode 30 can be positioned in side portions 15 s and anelectronics module 90 positioned in the center portion 15 c. Electrodes20 and 30 are positioned on opposite side portions 15 s as is shown inthe embodiment of FIG. 5 a; however other configurations are alsocontemplated such as the placement of electrodes 20 and 30 in each sideportion 15 s. Electronics module 90 can include a controller 93 whichmay correspond to controller 530 (shown in FIG. 6 c) and a power source97 which may correspond to power source 570 (shown in FIG. 6 b) and caninclude an electrochemical storage battery and circuitry for convertinga DC (direct current) signal from the battery(s) into an AC (alternatingcurrent) signal. The electronics module 90 includes a user activationdevice 91 such as a push-button or switch for initiating a drug deliverycycle to deliver a dose of an opioid or other therapeutic agent 51(e.g., an antiemetics). Other electromechanical activation devices 91known in the art are also contemplated. Typically, activation device 91is coupled to controller 93 (or other controller) so that signals 91 sgenerated by device 91 provide an input to the controller for initiatinga function such as initiation of a delivery period and/or delivery cycleof therapeutic agent 51. However, in additional or alternativeembodiments, activation device 91 may comprise an externally connecteddevice such as a push-button device that is electrically connected tomodule 90 (e.g., by a wire) and positioned and configured for easyaccess by the patient (e.g., a device that is attached to the patientbelt or may lie by the patent's bed side). In still other embodiments,activation device 91 may comprise a wireless device, such as a cellphone, pda or RF-enabled communication device that can be carried, wornor placed in close proximity to the patient. For such wirelessembodiments of device 91, device 91 and/or controller 93 may includevarious passwords or other codes to prevent accidental and/or otherunauthorized use.

Referring now to FIGS. 5 b-5 d, embodiments of a method for “on demand”drug delivery using a biphasic transdermal iontophoretic delivery system5″ will now be described. Embodiments of this method are applicable withvarious embodiments of the patch and electrode assemblies describedherein such as patch assembly 15 cp and 500. “Biphasic transdermaliontophoretic delivery” refers to the use of a transdermal iontophoreticdelivery system having a first and second phase of drug delivery. Insome embodiments, the first and second phase of drug delivery maycorrespond to a delivery period and a non-delivery period. The deliveryperiod in turn may correspond to a period of active transport of thetherapeutic agent (e.g., using a drive current) and the non-deliveryperiod to a period of active inhibition of such transport (e.g., using aholding current). As shown in FIGS. 5 b-5 d, before the initiation of adelivery cycle (e.g., by the patient, or other user) no or minimal agentis delivered as the agent is held within reservoir 21 by a holdingcurrent 320 described below. When the patient presses activation device91 this generates a signal 300 which is fed into the controller 93. Thecontroller 93 can include a control program or other logic 93 p forstarting a drug delivery period 340 upon receiving the signal 300. Thecontrol program 93 p then initiates the beginning of a drug deliveryperiod 340 by the flow of a first current known as a drug deliverycurrent 310 (also referred to herein as a drive current 310) which has apolarity and magnitude or other characteristic configured to repeltherapeutic agent 51 from the reservoir 21 and into the skin (thepolarity being the same in sign (i.e., positive or negative) to thecharge to that of the ionic form of therapeutic agent 51). The othercharacteristics of current 310 can include, without limitation one ormore of the voltage, frequency/period or shape of the waveform ofcurrent 310 (these characteristics can also be used for adjustment ofholding current 320 to perform its function).

Controller 93 keeps the delivery current 310 on for the delivery period340 to deliver a selected dose of the therapeutic agent 51 into the skinas shown by the delivery curve 350 (also referred to as deliveryprofile) in FIG. 5 d (the delivery period and delivery current can bestored in controller 93 and/or determined by program 93 p, for example,using the transfer function and other modeling methods described in theappended example). At the end of the delivery period 340, the controllerstops the delivery current 310 and starts a non-delivery period 330(also described herein as refractory period 330) by generating a holdingcurrent 320. Holding current 320 has a polarity and magnitude or othercharacteristic configured to retain agent 51 within reservoir 21 by theforce of electrostatic attraction (e.g., the polarity of the holdingcurrent 320 has the opposite sign as the charge of the ionic form of thetherapeutic agent) so as to prevent or minimize passive diffusion of thetherapeutic agent from the patch into the skin. Such minimal diffusionis shown in the non-delivery curve 360 in FIG. 5 d. Such passivediffusion would otherwise occur without the presence of attractive forcefrom the holding current 320. In particular embodiments, one or morecharacteristics of holding current 320 can be adjusted relative to thetype and concentration of the therapeutic agent 51 within solution 54and/or other property of solution 54 so as to assure that the holdingcurrent is sufficient to retain agent 51 within reservoir 21. Forexample, the magnitude of the current 320 can be proportionally orotherwise adjusted (e.g., geometrically) relative to the concentrationof therapeutic agent 51 within solution 54. For embodiments deliveringvarious nicotine salts described herein, holding current 320 can also beadjusted depending upon the particular nicotine salt and itsconcentration within solution 54. The current may be increasedproportionally or in another fashion relative to the concentration ofthe nicotine salt. The adjustment can be done at the factory, by themedical caregiver, pharmacist (e.g., when they mix up a particularnicotine salt into solution 54) or via software within controller 93.The adjustments can also be done dynamically over the course of adelivery cycle to account for changes in the concentration of agent 51within solution 54. In particular embodiments, a sensor may be employedto measure the concentration of agent 51 within solution 54 withinoutput of the sensor being fed as an input to controller 93. In relatedembodiments similar adjustments can be in the characteristics of current310 relative to the concentration of agent 51 in solution 54 or otherproperty of solution 54 so as to assure that sufficient agent 51 isdelivered out of reservoir 21 and into the patient's skin.

Also, during non-delivery period 330, the controller locks out orotherwise prevents the start of another delivery period so as to preventthe patient (or other person) from repetitively dosing themselves andthus over-dosing themselves. After the lockout period, the controllerthen allows the start of another delivery cycle. The controller can alsobe programmed or otherwise configured to only allow a maximum number ofadministered doses of agent 51 over a selected period of time, forexample, 12, 24 hours etc. In particular embodiments for the delivery oftherapeutic agents 51 p for the treatment of addiction and addictivecravings, such as nicotine compounds for the treatment of nicotinecravings, the maximum number of doses can correspond to 24, 40, 48, 60,80, 98 or 100 doses over a 12 or 24 hour period. The maximum number ofdoses is configured to keep the concentration (e.g., plasmaconcentration) of therapeutic agent within a therapeutic index (known inthe art) and prevent the dose from exceeding a maximum tolerated dosesuch as that which would cause or begin to cause respiratory depression,low blood pressure, slowed or fast heart rate and/or other adversephysiologic affects. Similarly, the maximum number of delivered dosesand/or lockout period can be selected to keep the rate of delivery oftherapeutic agent 51 to the patient below that which would cause suchadverse affects. The maximum number of doses and lockout period can bedetermined based on one or more parameters including without limitation,the therapeutic agent, the patient's age and weight, their condition andother therapeutic agents they are receiving (currently, previously or inthe future).

Referring now to FIGS. 6 a, 6 b, 6 c, 7 a and 7 b, in variousembodiments, a system 500 for iontophoretic transdermal delivery oftherapeutics agents 51 p for the treatment of addictive cravings and/orother therapeutic agents can comprise a skin conformable patch 505 andan electronics assembly 550. System 500 (also described herein as patchassembly 500) can be configured as an “on demand” transdermal deliverysystem 5′ and/or biphasic transdermal iontophoretic delivery system 5″as described herein. Patch 505 includes first and second electrodeassemblies 510 and 512 which can correspond to one or more embodimentsof electrode assemblies described herein. The materials used tofabricate the electrode portions of the assemblies can include variouscorrosion resistant materials such as graphite further described in U.S.patent application Ser. Nos. 12/824,146 and 12/824,147 (both filed Jun.10, 2010) which are fully incorporated by reference herein for allpurposes. Also, one or both of electrode assemblies 510 and 512 caninclude a pair 520 of tissue contacting ring shaped electrodes 521 and522 concentrically spaced or otherwise arranged to reduce edge effectsas is further described in U.S. patent application Ser. No. 12/832,011(filed Jul. 7, 2010) which is fully incorporated by reference herein forall purposes.

Electronics assembly 550 typically includes a housing 560 which engagespatch 505 so as to form patch assembly 500. Housing 560 includes abottom and top surface 561 and 562 respectively, with the bottom surface561 typically being the area of contact for engaging patch 505, thoughother arrangements are also contemplated. In particular embodiments, thehousing 560 can be configured to be detachably coupled to patch 505 viaone or more detachment elements 600.

Housing 560 can have a variety of shapes. In many embodiments, it caninclude a shaped contour 563 such as a curved shaped contour 564 (whichcan be for one or both of bottom surface 561 and top surface 562) thatis configured to correspond to the contour C of the skin surface SS atthe target tissue site TS where patch assembly 500 is placed such as thecontour of the patient's arm, leg or abdomen (e.g., on the front or sideof the stomach including below the waist line so as to not be visible).Contours 563 and 564 may: i) correspond to a standard contour for aparticular target site TS; ii) may come in different sizes and shapesfor different target tissue sites and sizes of patients; or iii) may becustom shaped for the particular patient and target tissue site. Also,the housing 560 can be conformable so as to at least partially conformto the contour C of the skin surface SS at the target tissue site TSwhere the patch 505 and housing 560 are placed (both when the patient isstill and when they are moving resulting in bending movement and otherdeformation of the skin such that the skin surface contour is a flexingcontour). Accordingly, in various embodiments, all or a portion ofhousing 560 can comprise various flexible polymers known in the art suchas various elastomeric polymers, e.g., silicone and polyurethane. Otherflexible polymers are also contemplated. The flexibility/conformabilityof the housing can also be configured to vary over the length of thehousing to meet the needs of the particular target tissue site TS. Forexample, the housing 560 can be configured to have the greatest amountof flexibility at its center portions 560 c (which can be achieved insome embodiments by putting a crimp or articulated zone 560 a near thecenter of the housing). Also, the flexibility profile of the housing 560can be matched or otherwise correlated to the shape and flexibilityprofile of the patch 505. For example, in particular embodiments, theflexibility/conformability of the housing can be configured forembodiments of the patch 505 having ring shaped electrodes 521 and 522.In these and related embodiments, housing 560 may have a structure whichinclude areas 566 of greater flexibility (e.g., less stiffness) whichmay approximately align with ring shaped electrodes 521 and 522 (orothers) such that the overall flexibility of the assembly 500 is notdecreased over these areas. Areas 566 can have a shape which correspondsto the shape of electrodes 521 and 522 (or other shaped electrodes),though the size of the areas can be different from the size of theelectrodes. Areas 566 can be achieved by decreasing the thickness of thehousing in these areas and/or the use of more flexible materials. Otherstructures for housing 560 including shaped areas 566 are alsocontemplated, such as structures which have oval shapes areas 566 oreven recessed areas 566.

Also in various embodiments, housing 560 cannot only be conformable, butalso have a profile 565 shaped and sized such that the entire patchassembly 500 can be worn beneath the user's clothing and can bend andflex sufficiently so that: i) it is not readily detached by pressure orforce from the user's clothing (due to movement of the clothes and/orskin), allowing the patch assembly 500 to stay on for extended periodswhen adhered to a tissue site underneath the user's clothes; and ii) isnot readily visible beneath the user's clothes. In various embodiments,the profile 565 of the housing can have a contour 564 (of one or both oftop and bottom surfaces 562 and 561) which corresponds to the contour Cof the surface of the patient's arm, leg, abdomen or other target tissuesite TS. Further, embodiments of the housing 560 can be sized, shapedand otherwise fabricated to bend and flex sufficiently to account formovement of the patient's skin when the patch assembly 500 is placed onthe patient's abdomen, arm, leg and other target tissue sites. In thisway, even when the patch assembly 500 is placed under clothes (or not),the assembly can remain sufficiently adhered/attached to the patient'sskin for an extended period of time so as to allow a desired dose of thedrug or other therapeutic agent 51 to be delivered. In variousembodiments, the time period can be up to 24 hours, up to three days, upto a week with even longer periods contemplated. Specific combinationsof a patch 505 and housing 560 can be configured for specific desiredattachment periods using one or more factors described herein (e.g.,flexibility surface area, etc.). For embodiments of the patch includingelemental iron, such configurations can allow the patch to remainsufficiently adhered to the patient's skin for a sufficient time todeliver a therapeutic dose of the desired therapeutic agent 51 such asan agent 51 p for the treatment of the particular addictive craving(e.g., nicotine for the treatment of nicotine craving from smoking orother tobacco addition). Similar configurations and methods can beemployed for delivery of other drugs and therapeutic agents described.

Further, one or more of the size and shape (e.g., shape of the housingbottom surface 561 such as oval, circular, dogbone etc.) and flexibilityof the housing 560 can be selected relative to one or more of the sizeand shape (e.g., shape of patch surface 505 s) and flexibility of patch505 such that when the patch assembly 500 is worn openly or beneath thepatient's clothes, the applied amount of force from the housing 560 tothe skin surface SS beneath the patch (due to movement of the patient'sskin) or the clothing to the skin surface beneath the patch 505 (due tomovement of the clothing or skin) is fairly uniform (e.g., there is asubstantially uniform force distribution with minimal areas of forceconcentration). In use, these and related embodiments serve to minimizethe amount of thermal, electrical or other injury to the skin from highcurrent densities and/or hot spots from such force concentrations.Additionally for embodiments using delivery of therapeutic agent(s) 51from embodiments of patch 505 having two more or electrode assemblies(e.g., assemblies 510 and 512) such configurations minimizing forceconcentrations (from skin movement etc.) also serve to minimize anyeffect on the delivery of therapeutic agent from the first electroderelative to the second electrode (or others). In particular embodiments,this can serve to minimize any effect on the delivery rate or totaldelivered amount of therapeutic agent from the first electrode assembly510 relative to the second electrode assembly 512 (or other electrodeassemblies).

In particular embodiments, such results can be achieved by matching theflexibility of the housing 560 to the patch 505 (either approximatelyequivalent or a selected amount higher or lower, e.g., 5 to 50%) as wellas configuring the surface area of the patch 505 to be large enoughrelative to the surface area of the housing 560 so as produce asnow-shoe like effect so as to evenly distribute any applied force tothe housing from clothing or other applied force (such as that due tomovement of the skin) over the entire surface area of the patch 505.Surface area ratios in the range of 1:1.5 to 1:10 (housing surface areato patch surface area) are contemplated, with specific embodiments of1:2, 1:3, 1:5.

In still other embodiments, the housing 560 or patch 505 may include apressures sensor 567, such as a solid state strain gauge which sensesthe amount of force applied by the user's clothes to the housing and/orpatch. Input from the pressure sensor can then be used to modulate(either increase or decrease) current delivered to the patch relative tothe applied force. The current can be modulated down to prevent thedevelopment of hot spots on the patch from excessive pressure ormodulated up to account for any increase in the electrical impedance ofthe skin due to the applied pressure.

Assembly 550 will typically include a power source 570 (also referred toherein as current source 570) and a controller 530 (e.g., amicroprocessor or like device) for controlling one or more aspects ofthe iontophoretic delivery of the agent to the skin. Controller 530 canalso include an integrated or separate power controller 535 forcontrolling the delivery of current to the skin. One or both of thecontrollers 530 and 535 can be coupled to an H-bridge or other currentswitching/limiting device 540 for limiting or otherwise controlling thedelivery of current to the skin. The housing will also typically includea cavity 580 for current source 570, such as a cylindrical shaped cavitywhich may be sized for standard size batteries such as AA or AAAbatteries. Other shapes for cavity 580 are also contemplated.

In various embodiments, current source 570 can comprise one or moreelectrochemical batteries including an alkaline, lithium, lithium-ionand like chemistries. For ease of discussion, current source 570 will bereferred to herein as battery 570 but other current sources are equallyapplicable. Battery 570 can also comprise a rechargeable battery knownin the art. The battery 570 can have a selected capacity to deliversufficient current/voltage to the skin for transdermal delivery of thetherapeutic agent for periods ranging from 2 to 24 hours or even longer.Power source 570 may also correspond to alternating current powersource. Accordingly, in embodiments including an electrochemicalbattery(s), power source 570 may include circuitry for converting a DCsignal from the battery(s) into an AC signal. Other power/currentsources 570 are also contemplated, such as various storage capacitorsand piezo-electric based energy harvesting devices.

The patch 505 will typically include one or more conductive areas 506for electrical coupling to conductive elements 591 on the electronicsassembly 550. The conductive areas 506 can be coupled to conductivetraces 590 placed on the patch surface 505 s or within the patch 505.The conductive elements on the electronics assembly 550 can be coupledto one or both of controller 530 and current source 570.

Detachment elements 600 can be spring loaded and can be configured to beengaged by the fingers of a user. In particular embodiments, detachmentelements 600 may include or be mechanically coupled to one or moreanchoring elements 601 such as a hook for anchoring into patch 505. Theanchoring elements 601 may also comprise adhesive areas placed on thehousing bottom surface 561 which engage the patch surface 505S.

In use, detachment elements 600 allow the user to attach and detach anelectronics assembly 550 to a selected patch 505. This allows theelectronics assembly 550 to be reused for multiple patches. In anexemplary embodiment of using system 500, the user can obtain aparticular patch 505, scan information about the patch using a bar codereader (or other indicia reading means) described below and then attachthe patch 505 to the assembly 550. When the user is done using the patch(e.g., such as when the desired amount of drug has been delivered) theuser then detaches assembly 550 from the patch 505 discarding patch 505.In particular embodiments, assembly 550 can include programming whichprovides a signal such as beep or other alarm indicating to the userwhen to remove the patch 505. As an alternative, the patch surface 505 scan include an indicator portion 507 which changes color or otherwiseprovides visible indicia 508 to the user when the required amount ofagent has been delivered to the skin. In one embodiment, the indicia 508can comprise a symbol or marking 509 that becomes visible when theamount of therapeutic agent 51 has been delivered. Visibility of themarking can be due to depletion of therapeutic agent 51 within patch 505and/or a chemical or electrochemical reaction within or on the patch.

In particular embodiments, the electronics assembly 550 can also includea bar code reader for reading a bar code printed on patch 505 forascertaining various information about the patch 505 including forexample, the type and amount of therapeutic agent 51 contained in thepatch, a desired delivery regimen, lot numbers (of the patch 505 and thetherapeutic agent 51) shelf life, expiration date and relatedinformation. In an additional or alternative embodiment, patch 505 maycontain a memory device (e.g. an EEPROM and the like) 506 which containssimilar information and is readable by electronics assembly 550 (e.g.,by controller 530). Assembly 550 may also contain a memory device 556for storing information (described above) which may be coupled tomicrocontroller 530. The information contained in memory device 556(e.g., type, dose and lot number of therapeutic agent 51) can be enteredat the factory and/or by the doctor or pharmacist. Also informationentry can be done directly or over a network such as the internet orcellular phone network or other like network. Other indicia readingmeans, for reading/detecting other indicia of information about patch505 are also contemplated. Such indicia reading means can include,without limitation, use of various RFID chips known in the art.

System 500 including patch 505 and assembly 550, can be sized and shapedto be placed in any number of locations on the patient's skin includingthe arm, leg or abdomen, back or other location. The particular materialproperties of the patch 505 and housing 560 (e.g., thickness, modulus ofelasticity, bendability, etc.) can also be so selected to allowplacement at the desired location. For example, more flexible materialproperties can be selected for placement of the system 500 over skinareas with greater amounts of bending by the user, such as the stomach.Also, patch 505 and assembly 550 can be packaged together, for example,as a kit 500 k (which can include instructions for use) wherein theassembly 550 is matched to patch 505 in terms of size, current source,programming mechanical properties etc. Further, a given assembly 550 canbe calibrated for such a group of patches 505 or patches 505 from aparticular lot number. In such embodiments, multiple patches 505 can beincluded with a particular assembly 550. In use, this allows the patientto obtain a complete supply of patches to meet the delivery requirementsfor a particular therapeutic agent 51 over a period of days, weeks, ormonths. Further, the assembly 550 can be programmed such that when thepatient is near the end of his or supply of patches 505, that theassembly will give the patient a message to purchase more patches. Inrelated embodiments, the assembly 550 can be configured to interfacewith the Internet and/or a mobile communication device such as cellphone, to send a message to the patient's pharmacy and/or doctor to doone or more of the following: i) renew the patient's prescription for aparticular therapeutic agent patch 505; ii) have an order for a supplyof the therapeutic agent patch 505 ready for the patient's pick up athis or her drug store; and/or iii) ship an order for the therapeuticagent patch 505 to the patient's house.

Referring now to FIGS. 8A through 8F, a discussion will be presented ofvarious waveforms 800 or current output variations (over time) and theircharacteristics which can be used to promote delivery or retention ofone or more therapeutic agents 51. Embodiments of these waveforms can beused for embodiments of the invention having a single or two or moreactive electrodes 20. Numerous embodiments described herein provide forwaveforms 800 that vary between a given polarity and zero, wherein atthat polarity, the current (e.g., current 310) causes the therapeuticagent 51 to be repelled into the skin. In other embodiments, thewaveforms 800 alternate between positive and negative polarity suchwaveforms are referred to herein as waveforms 801.

For embodiments having a waveform 801 alternating between a positive andnegative polarity, the waveform 801 can be a charged balanced waveform802 configured such that the current delivered to each electrodeassembly (e.g., assemblies 20 and 30) in use is a charged balanced ACcurrent. A charged balance AC current means over a given duration, theamount of current delivered to the skin at each polarity issubstantially equivalent. As used herein substantially equivalent meansthat two values are within 80% of one another, and more preferablywithin 90% or 99% over the period of one or more waveforms. By orientingthe waveform to alternate in a charged-balance fashion, electricaltoxicity or other damage to the skin can be reduced or minimized. Inother embodiments, an alternating current waveform is used that isoriented towards being balanced in charge, but some asymmetry may exist.

Embodiments of waveforms 800 described below are variable between aminimum and maximum value. Some embodiments of waveform 800, such asdescribed with FIG. 8 b, may alternate in charge value (i.e. includereverse polarity) such waveforms are referred to herein as alternatingcharge waveforms 801. In such embodiments, the current delivery may bebalanced in charge so that waveform 801 is a charged balanced waveform802 as described above.

FIG. 8 a illustrates a waveform 800 that includes an extended or longdrug delivery period or duration 840 (which may correspond to deliveryperiod 340 shown in FIG. 5 c), according to an embodiment. In someembodiments, the skin may be assumed to handle only a maximum amount ofcurrent in a given duration (maximum current delivery) (e.g. 80milliamps per minute). For a given amperage, the duration of the outputof an alternating power source (e.g., power source 100 described above)may be set so as to not exceed the maximum current delivery. Thedelivery duration 840 may be set to some portion or fraction (e.g. 50%for n=2) of the overall period of the current output I₁. For example, insome implementations, the maximum current delivery (I₁) is assumed to be80 milliamps for one minute. In such an implementation, the deliveryduration is set for 20 seconds on 4 milliamp output. Rather than switchto negative polarity, the output of the power source 100 may alternateto no amperage output (rather than switch polarity). While the waveform800 depicted in FIG. 8A is rectangular, various embodiments of waveforms800 may have alternative shapes (e.g. sinusoidal, trapezoidal), with thecurrent delivery corresponding to the area under the curve. In theexample shown by FIG. 8A, an alternating power source 100 initiates adelivery duration 840 on one electrode (e.g., active electrode 20), withdelivery durations being set by a current that has a polarity thatmatches that of the charge of the therapeutic agent. The current mayalternate to zero output, in which the drug delivery is substantiallyceased. Thus, the non-delivery duration 830 may coincide with no currentoutput, rather than reverse current. In other embodiments, non-deliveryduration 830 is achieved through the use of a current which has apolarity which is opposite to the charge of active agent 51 as describedbelow in the embodiment of FIG. 8 b and above in the embodiment of FIG.5 b (e.g., in the form of holding current 320).

FIG. 8B illustrates another embodiment in which the alternating powersignal outputs a symmetrical wave 803 such as symmetrical square wave804. FIG. 8B (and other waveforms illustrated herein) illustrates use ofcharge balanced waveforms 802 to deliver charge balanced alternatingcurrents. For example, symmetrical waveforms in polarity may beconsidered as charged balanced. Depending on the application, the periodP of the cycle of waveform 802 may be long (e.g. 20 minutes) or short (1/60 seconds). The delivery duration 840 may correspond to half of theperiod P of the waveform 802. In the implementation shown, a reversecurrent is used in the non-delivery duration 830, to actively preventagent delivery to the skin.

FIG. 8C illustrates another embodiment of the invention in which thealternating power signal outputs an asymmetrical wave 805 such as anasymmetrical square wave 806, in that the delivery duration 840 isdifferent than the non-delivery duration 830. More specifically, theasymmetrical square wave 805 may include longer delivery durations (t₁),followed by short(er) rest durations (t₂). The rest durations maycorrespond to periods of no current, or as shown, reverse current (I₂).In one application, the rest duration enables the skin layer torecuperate from the drug delivery in the prior duration (e.g., todissipate any heat, concentration of ions, or other by productsresulting from the delivery of current). As an alternative or variation,the rest period may follow a period where no current is applied to theskin layer, so as to enable the skin layer to recuperate fromapplication of current.

FIG. 8D illustrates another embodiment in which the alternating powersignal has a trapezoidal waveform 807, so as to include ramp-up and/orramp-down periods 808 and 809. As depicted, I₁ is the maximum currentoutput generated from an alternating power source (e.g. power source100). The ramp-up period 808 extends for a duration t_(r), that isselected for reasons that include enabling the user to physicallyaccustom to the application of current and/or delivery of therapeuticagent 51. The ramp-up period 808 may be long, to enable the ramp-upduration to be effective. In an embodiment, a ramp-down period 809 mayoptionally be implemented.

FIG. 8E and FIG. 8F illustrate alternative waveform variations includingcompound waveforms 813 in which high-frequency oscillations 811 aresuperimposed on a low frequency base waveform 810. The base waveform 810may have a period P₈₁₀ that lasts seconds or minutes, corresponding tooutput current to the electrode assemblies ranging from a maximum (e.g.,4 mA) to no current and/or reverse current. The high-frequencyoscillations reflect small variations in the current value at instancesin the period. The period P₈₁₁ of the high-frequency oscillations 811may be one or more magnitudes shorter than that of the base waveform. Asan example, the base waveform 800 may have a period P₈₁₀ ranging fromseconds to minutes, and the high-frequency oscillations of the waveformmay have a period that ranges between milliseconds and seconds. Theeffect of the high-frequency oscillations 811 is to reduce the effectsof the capacitive charge in the skin layer in receiving the therapeuticagent 51. The high frequency oscillations 811 may also be used tofacilitate transport of the therapeutic agent through the skin includingthe stratum corneum by causing oscillations in the movement of thetherapeutic agent as it travels through the skin so as to find pathwaysof least resistance through the skin. In such embodiments, the highfrequency oscillations may be adjusted to enhance this effect throughuse of modeling (e.g., pharmacokinetic modeling) and/or the patient'sage, skin type and skin location

The base waveform 810 may be selected for considerations such asdescribed in prior embodiments. For example, in FIG. 8E, the waveform813 includes a ramp-up time period 808. In FIG. 8F, the waveform 800 hasa delivery duration 840 that is switched to a non-delivery duration 830.An embodiment of FIG. 8F illustrates that the high-frequencyoscillations 811 may be generated to be present only during the deliveryduration 840.

Nicotine Applications

A discussion will now be presented on nicotine compounds which can bedelivered using one more embodiments of the invention (e.g., variouspatch and electrode assemblies and systems described herein) and methodsfor the transdermal delivery of those compounds using those embodiments.The forms of nicotine which may be delivered by one or more embodimentsof the invention include, without limitation, nicotine in its free baseform, its analogues and derivatives as well as various salts of nicotineand analogues and derivatives of those salts. Nicotine and its analoguesand derivatives as well as salts of nicotine will sometimes be referredto herein as nicotine compounds.

Nicotine Analogues

Nicotine analogues can include any substance having a nicotinergiceffect (i.e. substances which bind to and/or have an effect on thenicotinic receptors, (specifically neuronal type nicotinic receptors) asis known in the art. Nicotine analogues can include without limitation,enantiomers and isomers of nicotine, substituted nicotines (Cl, Br, I,N02, aryl, alkyl, etc.), oxidation products of nicotine, metabolicproducts of nicotine, compounds related to nicotine such as myosmine,nornicotine, anabasine, etc., and a variety of other compounds havingeither similar stereochemistry (conformation) and/or physiologicalactivity. Further description of nicotine analogues including methods oftheir manufacture may be found in U.S. Pat. Nos. 4,590,278 and 5,138,062which are incorporated by reference herein in their entirety.

Nicotine Salts

Exemplary pharmaceutically acceptable nicotine salts which can bedelivered by various embodiments of the invention can include nicotinesalts of the following: tartrate (e.g., nicotine tartrate and nicotinebitartrate) chloride (e.g., nicotine hydrochloride and nicotinedihydrochloride), sulfate, perchlorate, ascorbate, fumarate, citrate,malate, lactate, aspartate, salicylate, tosylate, zinc chloride,succinate, pyruvate, and the like; nicotine salt hydrates (e.g.,nicotine zinc chloride monohydrate), and the like. Additional organicacids that can form salts with nicotine include without limitation,formic, acetic, propionic, isobutyric, butyric, alpha-methylbutyric,isovaleric, beta-methylvaleric, caproic, 2-furoic, phenylacetic,heptanoic, octanoic, nonanoic, oxalic, malonic, and glycolic acid, aswell as other fatty acids having carbon chains of up to about 20 carbonatoms. Preferred nicotine salts include salts of hydrochloride,dihydrochloride, citrate, tartrate, hydrogen tartate, bitartrate,malate, salicylate and zinc chloride. Various embodiments of theinvention also contemplate delivery of one or more of the above salts inwhich nicotine is substituted with either a derivative or analogue ofnicotine. Further description of pharmaceutically acceptable nicotinesalts may be found in U.S. Pat. No. 7,387,788 which is incorporated byreference herein in its entirety. Among other factors a particularnicotine salt may be selected based upon its solubility (e.g., highervs. lower,), its rate of active transdermal iontophoretic transportacross the skin and its rate of passive transdermal diffusion across theskin. Solubility of the nicotine salt may be measured and/or determinedfrom the Merk Manual or similar reference. The solubility may also beadjusted using one or more buffering agent, antioxidants (e.g., citricacid) or excipients described herein. Rates of active transdermaldiffusion and passive transdermal diffusion may determined using themethods described in the Example Section appended hereto. Also suchmethods may be used to establish the drive current 310 and holding 320for a particular nicotine salt or nicotine analogue salt.

Weight Per Cent of Nicotine Salts in Aqueous Solution

For various embodiments of the invention in which patch assembly 15 cpcomprises one or more nicotine salts (or salts of nicotine analogues)described above, those salts can be dissolved in an aqueous or othersolution 54 (e.g., an aqueous alcohol solution) contained withinreservoir 21 or other portion of patch assembly 15 cp. The dissolvednicotine salt content of solids in the aqueous solution 54 can rangefrom about 1 to 50 weight (wt) %. In specific embodiments, the dissolvednicotine salt content is about 10 wt %, preferably above 10 wt %,preferably above 15 wt %, preferably from about 15 wt % to 30 wt %, morepreferably above 20 wt %, more preferably from 20 wt % to 30 wt %. Thespecific wt % can be adjusted based on one or more of the followingfactors: tissue contacting area of the patch assembly 15 cp, desirednicotine dose during a given delivery period (e.g., 0.5 to 3 mg),desired nicotine dose flux (e.g., mg/sec/cm² patch surface area),desired plasma concentration (e.g., desired nicotine plasmaconcentration (e.g., about 2 to 20 ng/(ml plasma, more preferably about2 to 10 ng/ml), and total number of doses to be delivered by a givenpatch assembly (e.g., 10, 20, 40, 50 etc.). Dose response curves may beused to adjust the weight percent of nicotine salt based on more on moreof these factors as well as for patient characteristics such as patientweight current cigarette use, physiologic measurement of the patient'scurrent level of habituation to nicotine, etc.

Use of Pharmaceutical Excipients

In various embodiments the aqueous solution 54 may also one or morepharmaceutical excipients to perform one or more functions. Suchexcipients can include for example a buffering agent to maintain the pHof solution in the physiological range of that found in skin so as toreduce any skin irritation from the nicotine salt or other nicotinecompound within the aqueous solution and/or to reduce any skinirritation as result of ionotophoresis. The buffering agent hassufficient buffering capacity and concentration in the solution andbuffering properties to maintain the pH of the aqueous solution 54 inthe range of 4 to 6, more preferably in the range of 4.5 to 5.5 and mostpreferably in the range of 4.6 to 4.8 as the natural pH of unwashedhuman skin has been reported to be 4.7. Suitable buffering agents caninclude organic and non-organic buffering agents. Exemplary inorganicbuffering agents include, but are not limited to, phosphate buffersolutions, carbonate buffers, citrate buffers, phosphate buffers,acetate buffers, sodium hydroxide, hydrochloric acid. Exemplary organicbuffering agents include, but are not limited to, lactic acid, tartaricacid, meglumine, monoethanolamine, diethylamine, triethylamine,diisopropylamine, aminomethylamine, trihydroxymethylaminomethane,tetrahydroxypropylethylenediamine. Other excipients may include a skinpermeability enhancer to improve the permeability of the skin to variousnicotine compounds, antioxidants to improve shelf life of the aqueoussolution 54. Further description of various skin permeability enhancersand antioxidants as well as other excipients which may be used in theaqueous solution 54 (e.g., various gelling agents) or other portion ofpatch assembly 15 cp may be found in U.S. Pat. No. 7,387,788.

Use of Hydrophillic Polymer Matrices

In some embodiments, the aqueous or other solution 54 is containedwithin a hydrophilic polymer matrix such as a hydrogel matrix. Thehydrogel matrix may be contained in reservoir 21, tissue contactinglayer 24 or other portion of an electrode/patch assembly such asassemblies 14 and 15 cp described herein. The nicotine (or analogue orderivative) salt-containing hydrogel can suitably be made of any numberof materials including a hydrophilic polymeric material, such as onethat is polar in nature so as to enhance the stability of the dissolvednicotine compound. Suitable polar polymers for the hydrogel matrixcomprise a variety of synthetic and naturally occurring polymericmaterials. In one embodiment, the hydrogel formulation comprises asuitable hydrophilic polymer, a buffer, a humectant, a thickener, waterand a water soluble nicotine or analogue or derivative salt. Thesuitable hydrophilic polymer may comprise a hydrophilic polymer matrixwhich in one or more embodiments may correspond to polyvinyl alcoholsuch as a washed and fully hydrolyzed polyvinyl alcohol (PVOH). Asuitable buffer includes an ion exchange resin which is a copolymer ofmethacrylic acid and divinylbenzene in both an acid and salt form. Oneexample of such a buffer is a mixture of Polacrilin (the copolymer ofmethacrylic acid and divinyl benzene available from Rohm & Haas,Philadelphia, Pa.) and the potassium salt thereof. A mixture of the acidand potassium salt forms of Polacrilin functions as a polymeric bufferto adjust the pH of the hydrogel to about pH 6. Use of a humectant inthe hydrogel formulation is beneficial to inhibit the loss of moisturefrom the hydrogel. An example of a suitable humectant is guar gum.Thickeners are also beneficial in a hydrogel formulation. For example, apolyvinyl alcohol thickener such as hydroxypropyl methylcellulose aidsin modifying the rheology of a hot polymer solution as it is dispensedinto a mold or cavity. The hydroxypropyl methylcellulose increases inviscosity on cooling and significantly reduces the propensity of acooled polymer solution to overfill the mold or cavity. In oneembodiment, the nicotine (or an analogue or derivative) salt-containinghydrogel formulation comprises about 10 to 15 wt % polyvinyl alcohol,0.1 to 0.4 wt % resin buffer, and about 1 to 2 wt % nicotine (oranalogue or derivative) salt. The remainder is water and ingredientssuch as humectants, thickeners, etc.

Nicotine Dosages

Many embodiments of the invention are configured to deliver doses of anicotine compound approximating the nicotine delivered by a singlecigarette. Most cigarettes contain about 1 to 3 milligrams of nicotinein the smoke inhaled. According to one study, the average amount ofnicotine delivered by a medium cigarette has about 1.1 mg (milligram) ina medium yield cigarette. Djordjevic M V et al. Doses of nicotine andlung carcinogens delivered to cigarette smokers. J Natl Cancer Inst.2000 Jan. 19; 92(2):106-11. The average dose delivered of nicotine perpuff has been reported to be in the range of 0.08 to 0.12 mg.Accordingly, various embodiments of patch assembly 15 cp can beconfigured to deliver doses of nicotine or other nicotine compound inthis range during a single delivery period with larger and smallerdosages contemplated. Further, the dose delivered during a deliveryperiod together with the number of delivered doses during a deliverycycle can be configured to deliver between 0.7 to 3 mg of nicotine (ornicotine analog or derivative) during a delivery cycle with specificembodiments of 0.8, 0.9, 1.0 1.1, 1.2, 1.4, 2 and 2.5 mg of nicotine (ornicotine analog or derivative). As is discussed herein, both the dosedelivered during a single delivery period and the total dose deliveredduring a delivery cycle can be adjusted for one or more patientcharacteristics and other factors described herein.

In various embodiments, suitable doses of nicotine (e.g., or nicotineanalogue or derivative) for administration to a patient over a deliveryperiod can include, for example, about 0.02 to 5 about milligrams, morepreferably about 0.05 to about 2.5 milligrams, more preferably about0.06 to about 2 milligrams, more preferably about 0.06 to 1 milligrams(mg), still more preferably 0.07 to 0.5 mg, and still more preferably0.08 to 0.12 mg. Specific doses during a delivery period can include0.08, 0.09. 0.10, 0.11 and 0.12 mg. For cigarette cessationapplications, a more preferred dose delivered during a delivery periodis about 0.1 milligrams of nicotine (or nicotine analogue) whichcorresponds to an average dose delivered from a single puff of acigarette. This or other nicotine dose may be titrated for the patient'ssmoking pattern (e.g., long deep inhales (higher dose) vs. fast puff(lower dose), number of cigarettes smoked per day, e.g., 10 vs. 20),type of cigarette smoked (low vs., high nicotine), patient weight orother characteristic of the patient (e.g., age, etc.). Similartitrations may be done for other forms of inhaled tobacco use such aspipe or cigar use or even electronic cigarette use. Also, the delivereddose during a delivery period may be re-titrated based on the patient'sprogress in their smoking cessation plan as is discussed below.

In various embodiments, between about 1 to 80 doses of nicotine (ornicotine analogue) may be delivered over a 24 hour period; for example,10, 20, 30, 40, 50, 60, 70 doses of nicotine can be delivered over a 24hour period. Adjustment may be made for burst mode delivery as describedherein. In one or more embodiments, a particular number of dosesdelivered in a set period such as a one hour, six hour, 12 hour or 24hour period can be limited, for example, so as to not exceed a totaldelivered dose of nicotine or nicotine analogue. Accordingly in variousembodiments, various lockouts may be programmed into system 5 and/orpatch assembly 15 cp to limit the number of doses and/or control theinterval between doses (e.g., the non-delivery period).

Burst Mode Delivery of Nicotine Compounds

According to one or more embodiments of the invention the profile of theof dose of nicotine compound delivered during a delivery period and/orcycle (herein “delivery profile”) can be configured to mimic orotherwise approximate the nicotine delivery profile 350 a a patientexperiences from smoking a cigarette or other form of tobacco use. Inuse, such an approach can reduce nicotine/cigarette cravings since thenicotine delivered during a delivery period/cycle mimics and/or moreclosely approximates that which the patient gets from the smoking of acigarette (e.g., the profile from each puff of the cigarette) or otherform of tobacco. Referring now to FIGS. 8 g-8 i, in many embodiments,for achieving such a mimicked delivery profile, the delivery curve orprofile 350 for particular nicotine compound corresponds to a series ofbursts 352 during a delivery period 340 resulting in a profile 350corresponding to delivered profile 350 a from smoking a cigarette orother inhaled form of tobacco as is shown in the embodiments of FIGS. 8g and 8 h. Collectively, bursts 352 comprise a burst pattern 351.Delivery in such a fashion, is described herein as “burst mode”delivery. The duration 353 of each burst 352, interval 354 betweenbursts and delivered dose of nicotine compound for each burst maycorrespond to a puff duration 355, puff interval 356, puff nicotine dosefor a particular patient so as to simulate a “puff to puff” delivery ofnicotine to the patient. This may be done for a cigarette, cigar, pipeor an electronic cigarette. Typically, the bursts 352 may have a squarewave shape 357, but they may also have a curve shaped 358 such as a halfsign wave 359 as is shown in the embodiments of FIG. 8 i. In variousembodiments, the number of bursts may be between 1 to 30, 2 20 and 2 to15. In specific embodiment the number of burst can be 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14 and 15. In preferred embodiments, the number ofburst corresponds to typical number of puffs taken by a patient and thusmay have a range between about 8 to 12 bursts. As is described below,one or more burst parameters, such as duration of burst, intervalbetween bursts and number of burst may be adjusted to reflect thesmoking pattern of a particular patient as determined using one or moreof the “smoking parameters” described herein. Other embodimentscontemplate other delivery profile to mimic or otherwise simulate thenicotine delivery during a particular type of inhaled or other form oftobacco use. For example, a burst pattern 351 may be superimposed on asteady state delivery of nicotine compound during a delivery period 340.In various embodiments, the patent's plasma nicotine levels or otherrelated measurement may be taken as the patient smokes a cigarette.According to one or more embodiments, the measurement can be made whenthe patient uses an electronic cigarette known in the art in orderbetter control the precision of the nicotine dose delivered during eachpuff. The measurements can then be used to better approximate in profile350 the actual delivery nicotine profile 350 a for a given patient whenthey smoke a cigarette or use another form of tobacco.

Adjustment of Nicotine Delivery Parameters

As is discussed above, the dose of nicotine delivered during a deliveryperiod can be adjusted based on one or more considerations describedherein. In addition to this parameter, other parameters which may beadjusted in various embodiments of the invention can include theduration of a delivery period, the duration of non-delivery period.Further for embodiments using pulsed delivery of a nicotine compound,additional parameters which can be adjusted include, amount of nicotinedelivered in a given pulse in a delivery period, the number of pulses ina delivery period. One or more of these parameters are referred toherein as the “nicotine delivery parameters” or “delivery parameters”.In various embodiments, the adjustment to the delivery parameters can bemade by the medical care provider, pharmacist or the patient. Inparticular embodiments to the delivery parameters can be made usingvarious physiological measurements of the patient which are correlatedto or otherwise indicative of the patient's current level of habituationto nicotine and/or the desire psychoactive effect. Such measurementsinclude for example, heart, blood pressure, skin conductance/resistance.This allows the medical care provider to fine tune the delivered dose orother delivery parameter to reflect the patient's current use and/orpsychoactive need for cigarettes or other inhaled nicotine product. Thisapproach serves to decrease any feelings of nicotine withdrawal thepatient may experience when they first stop smoking and switch to use ofone or more embodiments of patch assemblies described herein. In use,this approach serves to increase a patient's compliance with the smokingcessation program since the patient doesn't go through any immediatenicotine withdrawal. Instead, the nicotine doses delivered to thepatient can be gradually stepped down over a period of days, weeks oreven months.

Embodiments Employing Adjustment in Delivery Parameters for SmokingHabits of the Patient

Various embodiments of the invention also contemplate adjustment of adose of delivered nicotine or other delivery parameter based on thesmoking pattern and habits of the patient. A brief description will nowbe presented on those patterns. After a patient inhales smoke from acigarette nicotine within the smoke is transferred from the alveolar sacof the lungs into the blood vessels surrounding the aveloli enrichingthe blood in those vessels with nicotine. The nicotine-rich blood thenpasses within seconds from the lungs to the brain where acts to producetwo psychoactive effects: a stimulant and a relaxant depending in parton the concentration of nicotine in the blood. Smokers seeking astimulating effect will take short quick puffs, which produced a lowlevel of nicotine in the blood. Smokers wishing to relax will take deeppuffs, which produce a higher level of blood nicotine. Thus, dependingon the desired psychoactive effect, this can result in variation in oneor more parameters (herein “smoking parameters”) of the patient'ssmoking pattern. Such parameters can include, for example, the durationof each puff, puff volume, puff rate, the interval between puffs andtotal number of puffs. Values for a parameter will typically beconsidered to be average values determined by measurement and/orquestioning of the patient. In this way, the delivery profile ofnicotine compound delivered by embodiments of the invention can moreclosely approximate or mimic the nicotine delivery profile from thepatient's actual use of cigarettes (or other form of inhaled tobacco).In use, this approach can reduce nicotine cravings since the nicotinedelivered during a delivery period/cycle mimics (e.g., more closelyapproximates) that which the patient gets from the smoking of acigarette or other form of tobacco. In particular embodiments a numberof smoking parameters can be can be pooled together to model a smokingpattern to achieve a particular psychoactive effect desired by thepatient. For example, puff duration, puff volume and puff rate can bepooled together in a model of a stimulant seeking vs. a relaxing seekingsmoking pattern. The model can comprise a first, second order or otherorder polynomial equation, cubit spline etc. Each of the smokingparameters may comprise a coefficient of a particular order of theequation and may be weighted accordingly. Again in this way, byadjusting the delivered dose of nicotine to achieve a desiredpsychoactive effect of the patient, embodiments of the invention reducenicotine cravings and other symptoms of withdrawal. This in turn,improves compliance with a smoking cessation program and reduces thepotential for relapse upon completion.

Also for one or more embodiments using a pulsed delivery mode fornicotine compounds, the duration and number of pulses can be matched orotherwise correlated to the smoking pattern of the patient using one ormore of the smoking pattern parameters. For example, according to one ormore embodiments, the number of pulses can be matched or otherwisecorrelated (e.g., in rations of 1:2, 2:1 etc.) to the number of puffs bya patient as determined by measurement or questionnaire. According toother embodiments, more pulses having smaller amounts nicotine can beemployed for patients smoking for a stimulating effect and fewer pulseshaving larger amounts of nicotine for patients smoking for a relaxingeffect.

Embodiments Employing Adjustment in Delivery Parameters for Progress inSmoking Cessation

Also, one or more of the dose delivered during a delivery period,duration of a delivery period or dose delivered during a delivery cycle(the “dose delivery parameters”) may be reduced (herein the “reduction”)over time so as to wean the patient from the nicotine craving and,consequently, aid the individual in ceasing smoking. The reduction canbe made by the physician or other health care provider and can be madebased on various factors including one or more of the following progressfactors: i) how often the patient currently has nicotine cravings eachday, ii) the decrease in the number of cravings from the start of theirsmoking cessation program and/or a prior adjustment period, iii) howmany cigarette number of cigarettes they continue to smoke; and iv) thedecrease in the number of cigarettes they smoke from the start of theirsmoking cessation program and/or a prior adjustment period. Using one ormore of these four progress factors, the reduction in nicotine deliveredcan be titrated to the patient's individual progress in their smokingcessation program and in this way, facilitate a faster and moresuccessful smoking cessation program (e.g., where they have greatersuccess in kicking the habit not just at the end of the program but forextended periods there afterwards). The reduction can also be based onvarious physiologic measurements correlated to or otherwise indicativeof one or more of the following: i) the degree of nicotine withdrawalthey are experiencing, ii) the nicotine levels they are currentlyphysiologically habituated to, and iii) their decreased dependence onnicotine. Such measurements can include one or more of blood pressure,heart rate, respiration and like measurements. For example, withdecreased dependence, the patent's resting heart rate and blood pressuremay be expected to decrease when they have not have a dose of nicotinewithin several hours compared to the time when they just started theirsmoking cessation program. Contrarily, after they have had a dose ofnicotine, these parameters can be expected to increase relative to thetime when just started their smoking cessation program. The measurementsmay be taking before during or after receiving a dose of nicotinecompound either utilizing patch 15 cp and/or, electronic cigarette or anactual cigarette. Using the physiologic measurements, the reduction innicotine delivered can be titrated to the patient's physiologicalresponse to their smoking cessation program including their decreaseddependence on nicotine and in this way, facilitate a faster moresuccessful program. With either approach, a dose delivery parameter,such as dose of nicotine delivered during a delivery period, can bestepped down in set increments of for example 1, 5, 10%, etc. which aredetermined based on one or more of the progress factors and/orphysiological measurements. In yet another approach, a dose deliveryparameter such as dose of nicotine delivered during a delivery period,can be decreased in such increments based on time since the patientstarted their smoking cessation program. For example, the dose ofnicotine delivered during a delivery period, can be stepped down betweenabout 1 to 10% each week from start of their smoking cessation program,as an alternative between about 5% to 20% every two week or even everymonth. What the approach, the decrease can be adjusted so that so thatpatient does not experience any significant feelings of withdrawaland/or nicotine cravings, thus improving patient compliance with theprogram and reducing the likelihood of relapse.

Embodiments for Treatment of Other Psychoactive Conditions

Due to the psychoactive effects of nicotine, in various embodiments, themethods and apparatus described herein may also be adapted for treatmentof psychoactive and/or neurolgoical conditions such as schizophrenia,ADHD, headache, migraine headache. In such embodiments, one or more ofthe “delivery parameters” defined herein such as the dose deliveredduring a delivery period, rate of delivery (e.g., flux of drug throughthe skin) and duration of delivery period and non-delivery period can beadjusted for treatment of the particular psychoactive condition. Forexample, for ADHD, longer duration periods can be used to provide thepatient a steady delivery of therapeutic agent over an extended period,for example during a 12 hour period starting in the morning during thetime that the patient is in school and after school doing homework. Insuch applications the delivery period waveform can include a rapid riseat the beginning of the delivery period (e.g., in the morning) to getthe patient plasma concentration

EXAMPLES

Various embodiments of the invention are further illustrated withreference to the appended example which details the use of embodimentsof a biphasic transdermal iontophoreritic delivery system. Portions ofthe example are also described in a paper entitled: Biphasic TransdermalIontophoretic Drug Delivery Platform (McLaughlin, G. W, et al Conf.Proc. IEEE Eng. Med. Biol. Soc. 2011 August; 2011:1225-8) which isincorporated by reference herein for all purposes. It should beappreciated that this example is presented for purposes of illustrationand the invention is not to be limited to the information or the detailstherein. For example, while the example presented describes the deliveryof ferrous chloride, it should be understood that various embodiments ofthe invention can be used for the delivery of any number of compoundsusing this approach including, for example, various nicotine compoundssuch one or more nicotine salts, opioid such as methadone, antiemetics,(e.g., Dimenhydrinate) and other therapeutic agents.

Methodology

System Description: One embodiment of a system that was tested fordelivery of therapeutic agent comprised an active electrode, passiveelectrode, iontophoresis system and a programmer which are describedbelow.

Active electrode: This was constructed by using a DuPel Model#198809-001 (Empi, Inc., Clear Lake, S. Dak., USA) electrode with thebuffering agent removed and replaced with a teabag filled with twosheets of 3M gauze with 4.0 ml of solution. The solution was prepared bydissolving 1.2 g of FeCl2 (Sigma-Aldrich, St. Louis, Mo., USA) and 300mg of Poly-Ethylene Oxide (PEO, Mol. wt. 100k) into 4 ml of DI water.The active electrode area was 13.3 cm2.

Passive electrode: This was constructed using a DuPel Model#198809-001electrode with the buffering agent removed and replaced with a teabagfilled with two sheets of 3M gauze and 300 mg of Polyethylene Oxide(PEO) with 4 ml of DI water added. The active electrode area was 13.3cm2.

Iontophoresis system: This comprised a custom made unit that wascontrolled by a MSP430F428 (Texas Instruments, Dallas, Texas, USA)microcontroller. This microcontroller coordinated the activities betweenthe switch states of an H-bridge circuit in conjunction with a variablecurrent source. The H-bridge had a programmable voltage rail with aresolution of ˜650 mV steps and a maximum compliance voltage of 80V. Thevariable current source had a programmable current target with aresolution of ˜40μ×A with an upper limit of 5 mA. The microcontrollerwas able to update these values at a rate of 5 Hz along with measure andstore their values with a time stamp for data archival purposes. Two AAbatteries were used to power the system. These batteries were capable ofproviding up to 40 hours of operation under a standard therapy profile.FIG. 1 shows a picture of the system along with a simplified blockdiagram of the internals.

Programmer: This comprised a personal computer that was able to beinterfaced to the iontophoresis system via a USB cable. The applicationcode used to program the device was written in TCL/TK. This program wasable to set the therapy pulse duration and current value along with theinhibit pulse duration and current value. It was also capable ofspecifying the total therapy duration. In addition, the programmer wasalso able to retrieve the data stored in the unit for analysis.

Experimental Setup: Ten in-vitro test chambers were constructed out of ablock PTFE and filled with 120 ml of Hanks Buffered Salt Solution(HBSS). Freshly excised abdominal skin from a male Yorkshire pig (35 kg)was sectioned into 10 (100 mm×175 mm) pieces. Yorkshire pig skin wasused as it has been shown to closely mimic the properties of human skin.The subcutaneous fat beneath the dermis layer of the skin was removed sothat only the stratum corneum, epidermis, basal layer and dermis layersremained. The skin was then shaved and inspected for blemishes orscratches that might alter transport. Each test chamber had a piece ofskin placed on top. Particular care was taken to not damage theintegrity of the skin. The skin was affixed to the test chamber via 1¼″clips. The active and passive electrodes were then placed on the pigskin and attached to the iontophoresis system. All skin irregularitieswere avoided during this process.

The iontophoresis system was configured to provide a 6 hour therapysession. The first hour of the therapy session consisted of the systemin an inhibit mode with a current value of −3 mA. The second hour of thetherapy session was a drive mode with a current value of 3 mA. In hour 3and 4 the system was in the inhibit mode with a current value of −3 mA.In hour 5 the system was in a drive mode with a current value of 3 mAand in hour 6 the system was in an inhibit mode with a current value of−3 mA.

The experimental chambers were placed on magnetic stirrer-hotplates tomaintain the HBSS solution between 29° C. to 34° C., which kept thesurface of the pig skin between 28° C. to 33° C. Samples of 1 ml weredrawn every 15 minutes from the reservoir, using a 25 gauge needle. Anequivalent volume of HBBS solution was replenished to maintain the levelin the test chamber. During the data analysis, appropriate correctionfactors were used to compensate for this fluid replacement.

Upon completion of the therapy, the skin samples were visually examinedfor irritation and or staining. The samples were then photographed. Theconcentration of iron was quantified, after the required dilutions, byusing a standard colorimetric assay. The samples were added to an acidicbuffered reagent containing hydroxylamine, thiourea and Ferene (5,5′(3-(2-pyridyl)-1,2,4-triazine-5,6 diyl)-bis-2-furansulfonic acid,disodium salt). The acidic pH of the buffered reagent was used torelease the ferric iron, which is then reduced to ferrous form by thehydroxylamine. This ferrous iron then reacted with the Ferene producinga colored complex. The absorption of this ferrous-Ferene complex wasthen read at 595 nm using a spectrophotometer (Multiscan EX; ThermoElectron Corporation, Vantaa, Finland). The absorption spectrum provideda proportional relationship to that of the iron concentration within thesample. This assay method provides a lower limit of quantification of 50μg/dl.

Results

The average of the ten samples was taken for each 15 minute sampleperiod to obtain a mean cumulative density data set. This data set wasthen used as the measured output of the system to be identified, y(t).The input to the system was the known integral of the active portion ofthe therapy session, x(t). These sets of data were than used to identifythe system transfer function, h_(est)(t) which is shown in block diagramform in FIG. 9.

The transfer function h_(est)(t) of the system was estimated based onFourier transforms of the input and output signals on the system.

${H(\omega)} = {\frac{{X(\omega)} \cdot {Y(\omega)}}{{{X(\omega)}}^{2}} = \frac{{\hat{R}}_{xy}}{{\hat{R}}_{xx}}}$

An inverse Fourier transform was then taken of the resulting transferfunction. This data set was then cropped, limiting the memory of thesystem transfer function to a period of 10 samples or 2.5 hours. Theknown input data was then convolved with this transfer function toobtain the estimated cumulative system density response. This data wasthen analyzed to determine how well the predicted output matched themeasured output. This resulted in an R2 value of 0.912, confirming agood correlation between the model and the data.

Next, the derivative of the measured cumulative density data was taken.In order to obtain an accurate estimate of the derivative of the data afirst order least means squares fit was performed for each 4 samples ofthe data moving in a single sample step. The slope of this fit was thenused as the representative value for the derivative of the data. Thisdata was then analyzed using the same method as that of the cumulativedensity function data. This resulted in an R² value of 0.802, confirmingthat the predicted model correlated well with the estimated pulsatiledrug delivery model as shown in FIGS. 10 a and 10 b.

The measured results show a time lag of around 45 minutes between thestart of the therapy cycle and the detection of the FeCl₂ in the salinesolution. This time lag is expected in the in-vitro studies due to thetransport time required to traverse all the layers of the skin and reachthe saline bath. In an in-vivo study this lag would be expected to besubstantially smaller due to an active micro-capillary system just underthe basal layer, alleviating the need for the material to pass throughthe dermis layer.

CONCLUSION

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, the iontophoretic patchcan be modified in size, shape and dose of therapeutic agent fordifferent medical conditions, different tissue sites as well as forvarious pediatric applications. Additionally, the patch assemblies,methods and control algorithms can also be modified for skin type,therapeutic agent dose, as well as various pediatric applications.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as standalone elements. Hence, the scope of thepresent invention is not limited to the specifics of the describedembodiments, but is instead limited solely by the appended claims.

1. A method for transdermal iontophoretic delivery of a therapeutic agent to reduce nicotine cravings in a patient from an inhaled form of tobacco use, the method comprising: positioning at least one electrode assembly in electrical communication with the skin of the patient, the at least one electrode assembly including a skin contacting layer and a solution comprising the therapeutic agent, wherein the therapeutic agent passively diffuses into the skin without application of an external force; delivering a dose of a therapeutic agent from the at least one electrode assembly into the skin during a first period using a first current having a polarity and magnitude to repel the therapeutic agent out of the electrode assembly, a therapeutic agent delivery profile during the first period configured to mimic a nicotine delivery profile from the form of tobacco use; retaining the therapeutic agent in the at least one electrode assembly during a second period using a second current having a polarity and magnitude to retain the therapeutic agent in the electrode assembly such that delivery of the therapeutic agent into the skin during the second period is minimized, wherein the first period comprises a delivery period and the second period comprises a non-delivery period, which together comprise a delivery cycle; and delivering subsequent doses of therapeutic agent over subsequent delivery cycles.
 2. The method of claim 1, wherein the electrode assembly comprises a first electrode and a therapeutic agent reservoir electrically coupled to the first electrode and fluidically coupled to the skin contacting layer.
 3. The method of claim 2, wherein the electrode assembly further comprises a second electrode.
 4. The method of claim 1, wherein the inhaled form of tobacco use is cigarette smoking and the therapeutic agent comprises a nicotine compound.
 5. The method of claim 4, wherein an amount of nicotine compound delivered during the non-delivery period produces substantially no psychoactive effect in the patient.
 6. The method of claim 4, wherein about 1 to about 3 mg of nicotine compound is delivered over the course of multiple delivery cycles.
 7. The method of claim 4, wherein a dose of nicotine compound delivered during a delivery period or a delivery cycle is titrated using a patient characteristic.
 8. The method of claim 7, wherein the patient characteristic comprises at least one of the patient's weight, average number of cigarettes smoked per day or years of smoking.
 9. The method of claim 4, wherein a nicotine delivery parameter is adjusted using a parameter of a patient's smoking pattern.
 10. The method of claim 9, wherein the nicotine delivery parameter comprises at least one of a dose of nicotine compound delivered during the delivery period, dose of nicotine compound delivered during a delivery cycle, duration of a delivery period, duration of a non delivery period, or number of delivery cycles.
 11. The method of claim 9, wherein the delivery parameter comprises a least one of a puff duration, interval between puffs, or number of puffs per cigarette.
 12. The method of claim 1, wherein the therapeutic agent comprises a nicotine compound.
 13. The method of claim 12, wherein nicotine compound comprises a nicotine salt.
 14. The method of claim 13, wherein nicotine salt is selected from the group consisting of nicotine tartrate, nicotine citrate and nicotine hydrochloride.
 15. The method of claim 13, wherein the magnitude of the second current is proportional to a concentration of the nicotine in the solution.
 16. The method of claim 12, wherein nicotine compound comprises a nicotine analogue or salt of a nicotine analogue.
 17. The method of claim 12, wherein about 0.02 to about 0.2 mg of nicotine is delivered during the delivery period.
 18. The method of claim 17, wherein about 0.08 to 0.12 mg of nicotine is delivered during the delivery period.
 19. The method of claim 1, wherein at least one of the first or the second currents has a waveform having a square wave shape.
 20. The method of claim 1, wherein the therapeutic agent comprises a nicotine compound, the inhaled form of tobacco use is cigarette smoking and the nicotine delivery profile comprises a burst pattern having at least two bursts.
 21. The method of claim 20, wherein each burst has a substantially square wave shape.
 22. The method of claim 20, wherein each burst has a substantially half sign wave shape.
 23. The method of claim 20, wherein a duration of each burst is correlated to a puff duration by the patient when smoking a cigarette.
 24. The method of claim 20, wherein a delivered dose of nicotine compound during a burst is correlated to a delivered dose of nicotine during a puff by the patient when smoking a cigarette.
 25. The method of claim 19, wherein the number of bursts corresponds to a number of puffs by the patient when smoking a cigarette.
 26. The method of claim 20, wherein the burst pattern comprise between about 8 to 14 bursts
 27. The method of claim 19, wherein the burst pattern is initiated by a patient input from a patient activated device.
 28. The method of claim 1, wherein the therapeutic agent is a nicotine compound, the inhaled form of tobacco use is cigarette smoking and a dose of nicotine compound delivered during a delivery period is decreased after the start of a smoking cessation program by the patient to reflect the patient's progress in the program.
 29. The method of claim 28, wherein the dose of nicotine is decreased utilizing a smoking cessation progress factor.
 30. The method of claim 28, wherein the dose of nicotine is decreased utilizing a physiologic measurement correlated to the patient's current level of habituation to nicotine.
 31. The method of claim 30, wherein the physiological measurement comprises at least one of a heart rate or blood pressure.
 32. The method of claim 1, wherein the first and the second currents are charge balanced over the delivery cycle.
 33. The method of claim 1, wherein the magnitude of the second current is proportional to a concentration of the therapeutic agent in the solution.
 34. The method of claim 1, wherein the delivery period is initiated by a patient input.
 35. The method of claim 34 wherein the patient input device comprises a push-button device, a device positioned on the electrode assembly, a device externally connected to the electrode assembly or a wireless device.
 36. The method of claim 31, wherein a number of delivered doses of therapeutic agent is limited to a maximum number over a selected period.
 37. The method of claim 1, wherein the inhaled form of tobacco use is use of an electronic cigarette. 